Vaccine Types

Initially, the two main types of vaccine were live vaccines comprising attenuated strains of MAP and inactivated (killed) whole-cell vaccines. Later as vaccination technology advanced, fraction vaccines, subunit vaccines and vector DNA vaccines have been introduced in an attempt to address some of the problems that were identified in practice.

Although each particular vaccine has used a different formulation and different strain, the most commonly used strain has been strain 316F, which was laboratory adapted and attenuated by the original French researchers (Table 22.2). Live, inactivated or mixed MAP strains have always been used with a strong adjuvant for parenteral inoculation that nearly exclusively has been an oil or wax (olive oil, mineral oil, paraffin, etc.). Although in the early times attenuated vaccines were the standard, storing and handling issues and concerns with the spread of bacteria in the environment led to substitution with inactivated cells (Shin et al., 2008; Bull et al., 2013). It is generally considered that inactivated vaccines do not trigger long-lasting immune responses. However, parenterally administered water-in-oil formulations of inactivated MAP produce an inflammation nodule from where the antigens are slowly released permanently stimulating the host immune system in such a way that a single dose at an early age could be sufficient for the whole productive life of vaccinated animals (Bastida and Juste, 2011). The main commercial vaccines developed to date are water-in-oil emulsions with killed (Gudair^®, Silirum® and Mycopar®) (Bastida and Juste, 2011) or live-attenuated MAP (Neoparasec^®, LioJohne^®) (Tejedor, 1993; Molina et al., 1996) (Table 22.2). Vaccination with these types of vaccines has been shown to be the most cost-effective measure, reducing paratuberculosis pathology, MAP excretion and environmental contamination, while also improving production figures (Bastida and Juste, 2011).

However, fears of problems of interference with the immune tests used in bovine tuberculosis eradication programmes (Park and Yoo, 2016; Barkema et al., 2018) as well as loss of differentiation between infected and vaccinated animals (DIVA) have heavily weighted against vaccination. Other issues include a limited efficacy in preventing infection and, to a lesser extent, injection-site tissue damage and accidental self-inoculation. While generation of tuberculosis false positives among paratuberculosis-vaccinated individuals can be readily eliminated by using the official (OIE) comparative tuberculin test with both PPD-B and PPD-A or including M. tuberculosis complex-specific reagents (Perez de Val et al., 2012; Garrido et al., 2013; Park and Yoo, 2016;

Table 22.2. Vaccine types (Bastida and Juste, 2011); ^a(Park and Yoo, 2016; Shippy et al., 2017); ^b(Rosseels et al., 2006); ⁰(Bull et al., 2013).

	Route	Inactivation	Strain or antigen	Adjuvan t/carrier	Natural host studied	Months at vaccination	Country
Live-non- attenuated	P		High-passage strains	oil, none	cattle	1	USA
Live-attenuated	P		316F	POP, oil paraffin, oil, saline, lipid	Cattle, sheep, goat	0.25, 0.5-1, 1, 1.5, 2, 4, adult	UK, France, Australia, Greece, Spain, New Zealand, Denmark, Germany
	P		316F+2E	POP	Goat	1	Norway
	P		avirulent strain	POP	Cattle	0.5	USA
	O		K1 OreIA, KWpknG	Saline	Goat	8	USA
	P		989WAg906, 989WAg913, K10WAg915	Saline	None (mouse)
	P		K1 OIeuD, K10mpt64, K10secA2	Saline	None (mouse)
	P^a		KWsigL, KWsigH, KWIipN	Saponin-based (QuiIA), none	Goat (sigLonly in mouse)	1	USA
Inactivated (killed)	P	Heat, -	Mycobacterium avium avium Strain 18	Oil, oil + hlL-12	Cattle	0-1,0.25, 1,2-5.5	USA
	P	Heat	-	Oil, none, CFA, oil paraffin	Cattle, sheep, goat	1, 1-24, 3, adult	USA, Netherlands, Spain, Iceland, Greece
	P	Heat	316F	Oil, lipid	Cattle, sheep, goat	0.5, 0.75, 1, 1-4, 2,2-3,3,4,4-6, 8, 24, adult	Australia, New Zealand, Spain, USA, UK, India
	P	Heat	5889 Bergey	Oil	Cattle	1	Hungary
	P, O	Heat	Field strains	Oil, -, alum	Sheep, goat	0.25, 0.5, 0.75, 1, 1.75, 2, 3, 4-6	UK, India

368 R.A.

Juste et al.

Table 22.2. Continued

	Route	Inactivation	Strain or antigen	Adjuvan t/carrier	Natural host studied	Months at vaccination	Country
	P	Heat	Field strain CWD, CWC	Saponin-based (QS21), alum	Goat	0.25-1	USA
	P^b	Irradiation	ATCC19698	Oil	None (mouse)
Subunit	P		rec. hsp70	DDA	Cattle	1+11 (boost)	Netherlands
	P		rec. 85A, 85B, 85C, SOD	RAS	Cattle	0.3 + 1 (boost)	USA
	P		rec. 85A, 85B, 85C, SOD	RAS +blL-12	Cattle	0.3 + 1 (boost)	USA
	P		rec. 85A, 85B, SOD, 74 F	DDA, none	Goats	0.3 + 1 (boost)	USA
DNA	P		pVAX1 MEV encoding MAP genes	Gold microbeads	None (mouse)
	P		pEGFP-N1 MEV encoding p85A-Mav, p85A-BCG or hsp65	Saline	Sheep	5 + 5.7 (boost) +6 (boost)	Italy
	P		pV1 J.ns-tPA-his encoding MAP0586c or MAP4308c + protein boost	IFA (boost only)	None (mouse)
	pc		Ad5.HAV priming +MVA.HAV boosting (encoding MAP genes)	-	Cattle	2 + 3.5 (boost)	UK

-, not indicated; P, parenteral; O, oral; POP, paraffin + oliveoil + pumice; DDA₁ dimethyl dioctadecyl ammonium bromide; SOD, superoxide dismutase; hlL, human interleukin; blL, bovine interleukin; RAS, Ribi’s adjuvant system, consisting of bacterial monophosphoryl lipid A, trehalose dicorynomycolate and mycobacterial cell wall skeleton; CWD, cell wall deficient; CWC, cell wall competent; MEV, mammalian expression vector; CFA, complete Freund adjuvant; IFA, incomplete Freund adjuvant; HAV, priming with non-reρlicative human Adenovirus 5 followed by boosting with Modified Vaccinia virus Ankara delivery vectors expressing a fusion of MAP antigens.

Serrano et al., 2017; Roy et al., 2018), resolving the DIVA problem remains one of the main goals in paratuberculosis vaccine research.

Subunit vaccines or vectored DNA vaccine formulations based on immunogenic antigens have been developed with the goal of overcoming the above-reported potential diagnostic interference (Park and Yoo, 2016). A major role has been attributed to cell-mediated immunity in terms of protection from mycobacterial infection, and thus researchers have focused chiefly on antigens able to enhance this kind of immune response. The first reported paratuberculosis subunit vaccine evaluated in cattle consisted of recombinant heat shock protein 70 (Hsp70) adjuvanted with dimethyl dioctadecyl ammonium bromide for subcutaneous administration (Koets et al., 2006). Other antigens with potential for being included in a subunit vaccine include lipoproteins (LprG and MAP0261c), PPE family proteins (MAP1518 and MAP3184), superoxide dismutase and alkyl hydroperoxide reductases (AhpC, AhpD), however these have not been evaluated as vaccine candidates in target animals (Park and Yoo, 2016). Initial investigations on DNA vaccination using expression vectors or viruses to deliver immunogenic MAP antigens showed promising results (Park and Yoo, 2016). According to interferon-gamma expression levels and other microbiological and pathological parameters, vaccination with plasmids encoding for 85A-BCG and Hsp65 seemed to elicit strong protective immune responses against MAP in sheep (Sechi et al., 2006). A prime-boost vaccination strategy using non-replicative human Adenovirus 5 (prime) and Modified Vaccinia virus Ankara recombinant for MAP-specific antigens (HAV) showed a degree of protection against challenge in a calf model as assessed by different immunological markers and bacterial faecal shedding, while no cross-reactivity with tuberculin was observed and differentiation of vaccinated animals was enabled by a DIVA test (Bull et al., 2014). Despite promise, the results indicate that these subunit or DNA vaccines have been less effective than was expected in terms of protection. This research line remains still active since more subunit vaccines have been proposed as having potential to prevent infection (Barkema et al., 2018; Chapter 23, this volume).

Recent research on human anti-tuberculosis vaccines seemed to indicate that live genetically modified attenuated vaccines could better stimulate both cellular and humoral immune responses providing better protection than other formulations. Therefore, the search for suitable attenuated strains as vaccine candidates regained researchers’ interest (Rathnaiah et al., 2017). Many live-a ttenuated vaccine candidates have been produced by phage-mediated, transposon and allelic exchange mutagenesis (Park and Yoo, 2016). Whole-genome expression studies led to the identification of exploitable MAP genes for the construction of targeted mutant MAP strains as live-attenuated vaccine candidates (Wu et al., 2007). Some of these vaccines induced strong protection in the mouse model, protection that was not replicated in other studies using the goat model (Barkema et al., 2018). Very recently, superior protection has been reported for a live- attenuated lipN mutant as it was able to eliminate faecal shedding from experimentally challenged goats (Shippy et al., 2017). However, the efficacy of such knockout vaccine candidates needs to be confirmed in cattle, under natural conditions, on a large scale and in long-term evaluation studies. In spite of their potential, disadvantages of live-attenuated vaccines need to be assessed: shedding of living and mutated microorganisms to the environment, virulence recovery, possible severe reactions, activation of immune modulation pathways, stability issues, producing-storinghandling difficulties, diagnostic interference and the lack of DIVA tests.

22.4

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Source: Behr Marcel A., Stevenson K., Kapur V. (eds.). Paratuberculosis: Organism, Disease, Control. 2nd edition. — CAB International,2020. — 439 p.. 2020

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